The Melanocortinergic Pathway Is Rapidly Recruited by Emotional Stress and Contributes to Stress-Induced Anorexia and Anxiety-Like Behavior
Abstract
Neurons producing melanocortin receptor agonist, -MSH derived from proopiomelanocortin, and antagonist, agouti-related protein, are known to be sensitive to metabolic stress such as food deprivation and glucoprivation. However, how these neurons respond to emotional/psychological stress remained to be elucidated. We report here that acute emotional stressors, i.e. restraint and forced swim, evoked mRNA expression of c-fos, a neuronal activation marker, in a high percentage of proopiomelanocortin neurons (up to 53% for restraint stress and 62% for forced swim), with marked variations along the rostro-caudal axis of the arcuate nucleus. In contrast, only a small population of agouti-related protein neurons in this brain region was activated. These neuronal activation patterns were correlated with behavioral reactions. Both stressors suppressed feeding and induced anxiety-like behavior in the elevated plus-maze test, as reflected by a reduction in the percentage of entries and time spent in the open arms. Central pretreatment with SHU9119, a melanocortin receptor antagonist, dose dependently attenuated the anorectic and anxiogenic effects elicited by acute restraint or forced swim. These results indicate that the melancortinergic pathway can be rapidly recruited by acute emotional stress, and that activation of melanocortin signaling is involved in mediating stress-induced anorexia and anxiety.
Introduction
THE CENTRAL MELANOCORTIN system consists of the agonist, -MSH, a proopiomelanocortin (POMC) cleavage product, the endogenous antagonist agouti-related protein (AgRP), and their common melanocortin receptors, melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R). This system is well studied for its functions in the control of eating behavior and body weight. -MSH and AgRP have opposite effects on food intake and body weight. -MSH inhibits appetite and decreases body weight gain, whereas AgRP stimulates eating and increases body weight gain (1, 2, 3).
Emerging evidence suggests functional interactions between the endogenous melanocortin system and the stress system. Anatomical studies demonstrate that -MSH and AgRP neurons innervate a variety of brain regions that have been well characterized in stress reactions (4). When administered centrally, -MSH and its analogs mimic stress-induced behavioral responses such as excessive grooming (5, 6), decreased exploration in a novel and fearful environment (7), and reduced food intake (8, 9). However, the physiological role of endogenous melanocortin signaling in behavioral responses to stress remains to be elucidated.
Stressors can be grouped into two major categories, i.e. psychological/emotional stressors and physiological stressors, based upon their "processive" and "systemic" natures, with the former defined as limbic sensitive and the latter as limbic insensitive (10, 11, 12). Although these two types of challenges converge to activate a common response system, e.g. hypothalamo-pituitary-adrenal axis, they involve distinct neuronal circuits, and lead to different behavioral and physiological outcomes (10, 12). It is well known that POMC and AgRP neurons located in the arcuate nucleus respond inversely to metabolic stress, such as food deprivation and glucoprivation (13, 14, 15, 16). By contrast, little is known about how POMC and AgRP neuronal pathways respond to psychological/emotional stress.
Previous studies have classified restraint and forced swim as psychological/emotional stressors based upon the expression patterns of immediate early genes in the brain after stress administration (10, 11, 12, 17, 18). These two stressors were used in the present study to determine the role of melanocortin signaling in stress responses. This is based upon the following considerations] Involvement of melanocortin signaling in behavioral responses to acute emotional stress
The functional role of predominant activation of POMC neurons was investigated by examining the effects of melanocortin signaling on behavioral responses to acute emotional stress. A large body of evidence shows that exposure to emotional stress exerts anorectic effects in rodents and humans (41). Given that central administration of POMC-derived melanocortin receptor agonist -MSH and its analog Melanotan II (MTII) elicits potent inhibition of food intake (9, 42, 43, 44, 45, 46, 47), the predominant activation of the central melanocortinergic pathway may underlie the mechanism of emotional stress-induced anorexia. To test this we blocked central melanocortin receptors MC3R and MC4R using SHU9119 before exposure to stress. Acute restraint and forced swim stress-induced anorectic effects were prevented by pretreatment with SHU9119. SHU9119 binds to both MC3R and MC4R, the two primary central melanocortin receptors (44). However, the reversal of stress-induced anorexia by SHU9119 is believed to be mediated by MC4R because disruption of MC4R eliminates feeding responses to melanocortins and its analogs (48). Furthermore, the feeding effect mediated by MC4R has been restricted to specific brain regions (49). The PVN is likely to be the key neuroanatomical substrate for MC4R functions in the control of food intake (49). The activated POMC neurons and subsequent -MSH release in the PVN may mediate stress-induced anorexia. Future studies will address whether blocking MC4R specifically in the PVN can reverse stress-induced anorexia.
Another behavioral consequence of emotional stress is the induction of anxiogenic-like behavior. We show that acute restraint and forced swim stress induce anxiety-like behavior as indicated by decreased percentages of open arm entries and time spent in the open arms in the elevated plus-maze test. This stress behavioral reaction temporally coincides with POMC neuronal activation. It has been reported that enhancing central melanocortin signaling by administering exogenous -MSH and its analogs mimics stress-induced anxiogenic effects. For instance, icv injection of -MSH and MTII reduces time spent in the open arms in the elevated plus-maze test (50), and the number of licking periods in Vogel test (51). Our observations that the blockade of central melanocortin receptors with SHU9119 attenuated restraint and forced swim stress-induced anxiety-like behavior support the hypothesis that anxiogenic-like behavioral responses to emotional stress are mediated via activation of the central melanocortinergic pathway.
One candidate brain area that may act as a relay for enhanced arcuate POMC neuronal activity and anxiety-like behavior induced by emotional stress is the medial amygdala. This nucleus is a recipient of -MSH/POMC projections and expresses high levels of melancortin receptors (4, 52, 53). There exists an additional POMC neuronal cell population located in the nucleus of solitary tract. However, -MSH/POMC fibers in the medial amygdala are likely derived from POMC neurons in the arcuate nucleus instead of the nucleus of solitary tract. This assumption is based upon the finding that arcuate lesions almost completely eliminate -MSH immunoreactivity in the amygdala (54). Evidence suggests that the medial amygdala is a critical area for emotional processing (55, 56, 57). It has been shown that the medial amygdala is particularly sensitive to emotional/psychological stress (11, 12, 18), and pharmacological manipulations of this anatomical division alter the anxiety state (58, 59).
Emotional stress can trigger anorexia and anxiety in humans (20, 21, 22, 23, 24, 25). However, the neurobiological basis of this comorbidity between anorexia and anxiety is poorly understood. The results of this study provide evidence suggesting that increased central melanocortin signaling may be involved in the mechanisms underlying emotional stress-induced anorectic and anxiogenic effects.
so using bremelanotide will cause anxiety? I have pretty severe anxiety and it kills my libido when getting intimate. I was hoping bremelanotide would "brute force" my way around the anxiety.
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